P494: A FIRST-IN-HUMAN STUDY OF CD123 NK CELL ENGAGER SAR443579 IN RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA, B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA OR HIGH RISK-MYELODYSPLASIA
Authors: Anthony Selwyn Stein, Mojca Jongen-Lavrencic, Sylvain Garciaz, Gerwin A Huls, Abhishek Maiti, Nicolas Boissel, Stephane De Botton, Shaun Fleming, C. Michel Zwaan, David C. de Leeuw, Pinkal Desai, Martha Lucia Arellano, David Avigan, Saskia Langemeijer, Kyle Jensen, Timothy Wagenaar, Gu MI, Giovanni Abbadessa, Ashish Bajel
Journal: HemaSphere (2023)

Background: SAR’579 is a trifunctional natural killer (NK) cell engager targeting CD123 antigen and co-engaging NKp46 and CD16a on NK-cells. SAR’579 facilitates the formation of a cytolytic synapse between NK-cells and CD123-positive tumor cells leading to NK-cell activation and tumor cell killing. Aims: To report preliminary safety and efficacy data of SAR’579 from a phase 1/2 trial in patients with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell acute lymphoblastic leukemia or high risk-myelodysplasia (NCT05086315). Methods: SAR’579 was administered intravenously twice weekly or once weekly (QW), depending on the dose level (DL) for the first 2 weeks of cycle 1 and then weekly for rest of induction cycles. A patient receives approximately three 28-day induction cycles with patients achieving a complete remission (CR) or incomplete hematologic recovery (CRi) per International Working Group criteria transitioning to a 56-day maintenance period with dosing approximately every 29 days. The primary objectives were to establish safety/tolerability and anti-leukemic activity (composite complete remission [CRc] = CR+CRi). Results: With a cutoff date of January 27, 2023, total 23 patients with R/R AML across 6 DLs (3 patients DL1 and 4 each in DL2 - DL6) were included in the safety population. The median age was 70 years (range: 21 - 80) with 9 patients (39.1%) reporting prior hematopoietic stem cell transplantation (HSCT) and 16 (69.6%) had prior exposure to venetoclax. Patients received a median of 2 cycles (range: 1 – 7) for median duration of 7 weeks (range: 1 - 25) and escalating doses of SAR’579 between 10 - 3000 µg/kg/dose in cycle 1 and 100 - 3000 µg/kg QW for the rest of induction cycles. No dose limiting toxicities (DLTs) were observed among the 21 DLT-evaluable patients, until highest dose of 3000 µg/kg QW. The most common treatment emergent adverse events (TEAEs) included infusion-related reactions (n = 10 [43.5%]) and nausea (n = 7 [30.4%]). TEAEs were reported in 22 patients (95.7%) with grade 3/4 adverse events (AEs) in 18 (78.3%) and treatment-related AEs in 16 patients (69.6%), respectively. There were 2 cases of cytokine release syndrome (n=1 grade 1 and n=1 grade 2) and no case of immune effector cell-associated neurotoxicity syndrome. No patient reported TEAE leading to permanent discontinuation of SAR’579. The CRc rate was 13.0% (3/23 patients evaluable for response). In DLs with a highest dose of 1000 µg/kg QW, 3/8 (37.5%) patients achieved a CR (2 CR/1 CRi). The median time to first CR/CRi was 16.1 weeks 95% confidence interval (8.1 – Not Estimable [NE]), and the median duration of CR/CRi is NE due to limited follow-up time. Summary/Conclusion: SAR’579 was well tolerated up to doses of 3000 µg/kg QW with observed clinical benefit in patients with R/R AML. The trial continues to accrue patients. Keywords: Acute lymphoblastic leukemia, Myelodysplasia, Acute myeloid leukemia, NK cell